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Combination Chemotherapy and Surgery With or Without Isotretinoin in Treating Young Patients With Neuroblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00499616
Recruitment Status : Completed
First Posted : July 11, 2007
Results First Posted : June 27, 2017
Last Update Posted : July 6, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Study Description
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Brief Summary:

RATIONALE: Drugs used in chemotherapy, such as carboplatin, cyclophosphamide, etoposide, and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Isotretinoin may help neuroblastoma cells become more like normal cells, and grow and spread more slowly. Giving combination chemotherapy before surgery may make the tumor smaller and make it more likely that the tumor can be surgically removed. It is not yet known what is the minimal amount of chemotherapy needed to achieve sufficient tumor shrinkage to control intermediate risk neuroblastoma and prevent tumor recurrence or metastases.

PURPOSE: This phase III trial is designed to reduce therapy for patients with favorable biology intermediate risk neuroblastoma by decreasing the number of chemotherapy cycles administered and by allowing for up to 50% residual tumor volume for patients with localized disease.


Condition or disease Intervention/treatment Phase
Neuroblastoma Drug: carboplatin Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: etoposide Drug: topotecan hydrochloride Drug: Isotretinoin Procedure: Surgery Drug: Filgrastim Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 464 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma
Actual Study Start Date : October 8, 2007
Actual Primary Completion Date : June 30, 2014
Actual Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

Arms and Interventions
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Arm Intervention/treatment
Experimental: Group 2 (chemotherapy, surgery)
2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.
 Drug: carboplatin
Given IV
Other Names:
  • Paraplatin
  • NSC #241240

Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC #26271

Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • Adriamycin
  • NSC #123127

Drug: etoposide
Given orally
Other Names:
  • VePesid
  • VP-16
  • NSC #141540

Drug: topotecan hydrochloride
Given IV
Other Names:
  • SKF-104864
  • Hycamtin
  • NSC #60969

Procedure: Surgery
With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.

Drug: Filgrastim
Administered subcutaneously or by IV beginning 24-48 hrs after the last dose of chemotherapy & continuing daily until the ANC is greater than or equal to 1500 following the myelosuppressive nadir . Supportive care given to stimulate neutrophil recovery following chemotherapy and to shorten the duration of chemotherapy-induced neutropenia. On ANBL0531 the use of filgrastim was required for patients less than 60 days of age and was optional for other patients.
Other Name: Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen, NSC #614629
Experimental: Group 3 (chemotherapy, surgery)
4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
 Drug: carboplatin
Given IV
Other Names:
  • Paraplatin
  • NSC #241240

Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC #26271

Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • Adriamycin
  • NSC #123127

Drug: etoposide
Given orally
Other Names:
  • VePesid
  • VP-16
  • NSC #141540

Drug: topotecan hydrochloride
Given IV
Other Names:
  • SKF-104864
  • Hycamtin
  • NSC #60969

Procedure: Surgery
With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.

Drug: Filgrastim
Administered subcutaneously or by IV beginning 24-48 hrs after the last dose of chemotherapy & continuing daily until the ANC is greater than or equal to 1500 following the myelosuppressive nadir . Supportive care given to stimulate neutrophil recovery following chemotherapy and to shorten the duration of chemotherapy-induced neutropenia. On ANBL0531 the use of filgrastim was required for patients less than 60 days of age and was optional for other patients.
Other Name: Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen, NSC #614629
Experimental: Group 4 (chemotherapy, surgery, antineoplastic therapy)
8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients < 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
 Drug: carboplatin
Given IV
Other Names:
  • Paraplatin
  • NSC #241240

Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC #26271

Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • Adriamycin
  • NSC #123127

Drug: etoposide
Given orally
Other Names:
  • VePesid
  • VP-16
  • NSC #141540

Drug: topotecan hydrochloride
Given IV
Other Names:
  • SKF-104864
  • Hycamtin
  • NSC #60969

Drug: Isotretinoin
Given orally
Other Names:
  • 13-cis-retinoic acid
  • RO-43
  • 780
  • Accutane
  • Amnesteem
  • Claravis
  • Sotret
  • NSC#329481

Procedure: Surgery
With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.

Drug: Filgrastim
Administered subcutaneously or by IV beginning 24-48 hrs after the last dose of chemotherapy & continuing daily until the ANC is greater than or equal to 1500 following the myelosuppressive nadir . Supportive care given to stimulate neutrophil recovery following chemotherapy and to shorten the duration of chemotherapy-induced neutropenia. On ANBL0531 the use of filgrastim was required for patients less than 60 days of age and was optional for other patients.
Other Name: Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen, NSC #614629
Experimental: Non-intermediate risk enrolled on intermediate risk trial
The no treatment group assignment patients may have received some treatment on ANBL0531 but they were not evaluable on this study due to being non-intermediate risk and hence did not receive a treatment assignment on ANBL0531.
 Procedure: Surgery
With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.


Outcome Measures
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Primary Outcome Measures :
  1. Overall Survival (OS) Rates [ Time Frame: 3 years ]
    OS time is calculated from date of enrollment until death, or until last contact if the patient is alive.

  2. Definitive Determination of the Prognostic Ability of 1p and 11q [ Time Frame: At baseline ]
    Addressed by a descriptive comparison of the EFS and OS rates for patients with 1p loss vs without 1p loss, and for those with unbalanced 11q vs normal 11q.

  3. Comparison Between Reduce Intensity of Therapy for Patients With Stage 4 Neuroblastoma and Favorable Biological Features and Patients < 1 Year of Age With Stage 4 Neuroblastoma Treated on COG-A3961 [ Time Frame: Up to 3 years ]
    Addressed by the interim stopping rule and the comparison, by INSS stage, to the historical EFS rate of the analogous cohort of patients < 1 yrs of age.

  4. Comparison Between Reduce Intensity of Therapy for Patients With Unfavorable Histology Neuroblastoma and Patients Unfavorable Histology Neuroblastoma Treated on COG-A3961 [ Time Frame: Up to 3 years ]
    Addressed by the interim stopping rule and the comparison, by INSS stage, to the historical EFS rate of the analogous cohort of patients < 1 yrs of age

  5. Reduced Surgical Morbidity for Patients With Stage 4S Neuroblastoma [ Time Frame: Up to 3 years ]
    Descriptive analyses of the proportion of stage 4S infants that experience a surgical or post-operative event.

  6. Outcome of Patients With Stage 4S Neuroblastoma Who Are Unable to Undergo Biopsy for Biology-based Risk Assignment [ Time Frame: From baseline to up to 10 years ]
    Kaplan-Meier curves and lifetables of Event Free Survival (EFS) and Overall Survival (OS) rates will be generated to describe the outcome of the stage 4S infants unable to undergo biopsy.

  7. Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Event Free Survival (EFS) [ Time Frame: Up to 10 years ]
    To test the predictive ability of the extent of surgical resection for EFS, log-rank tests will be performed comparing complete surgical resection vs. without complete surgical resection.

  8. Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Overall Survival (OS) Rates [ Time Frame: Up to 10 years ]
    To test the predictive ability of the extent of surgical resection for OS, log-rank tests will be performed comparing complete surgical resection vs. without complete surgical resection.

  9. Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Surgical Complication Rate [ Time Frame: Up to 10 years ]
    To test for the association of the extent of surgical resection (CR vs <CR) with surgical complications rate (complications of any kind vs no complications at all), a chi-square test will be performed.


Secondary Outcome Measures :
  1. Second-event-free Survival (E2FS) [ Time Frame: From the time of the first progressive, non-metastatic event until the subsequent occurrence of relapse, progressive disease, secondary malignancy, or death; up to 3 years ]
    E2FS (from time of first event) will be calculated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy.

  2. Second-Overall Survival [ Time Frame: From the time of the first progressive, non-metastatic event; up to 3 years ]
    OS (from the time of first event) will be calculated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy.

  3. Biological Surrogate Markers [ Time Frame: At baseline and surgery ]
    Multivariable analyses will be performed to identify variables of prognostic interest.

  4. Neurologic Symptoms [ Time Frame: At baseline ]
    Percentage of patients with neurologic symptoms will be calculated. Includes patients with paraspinal or intraspinal tumors, including epidural tumors with or without spinal cord compression. Neurologic symptoms include back or extremities neurologic symptoms, motor deficit, abnormal sensation, abnormal bladder/bowel sphincteric function, chronic pain in back or extremities, scoliosis, kyphosis, or clinically relevant/functional abnormality in size or contour of leg or foot.

  5. Association Between Surgical Biopsy Technique With Adequacy of Tissue Acquisition for Biologic Studies, and With Complications Associated With the Biopsy Procedure [ Time Frame: During and after surgery ]
    A chi-square test will be performed.

  6. Image Defined Risk Factor (IDRF) [ Time Frame: At baseline ]
    Percentage of patients with presence of one or more IDRFs will be calculated. IDRFs describe anatomic features which may make surgical resection more difficult.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed neuroblastoma, ganglioneuroblastoma, or ganglioneuroma/maturing subtype

    • Newly diagnosed disease
    • Intermediate-risk disease
    • Needle biopsies or involved bone marrow are not sufficient for INPC histologic classification

  • Meets 1 of the following criteria:

    • Group 2

      • International Neuroblastoma Staging System (INSS) stage 2A/2B; < 50% resected or biopsy only; ≤ 12 years of age; MYCN-not amplified (NA); any histology and ploidy; normal 1p and 11q
      • INSS stage 3; age < 365 days; MYCN-NA; favorable histology (FH); hyperdiploid (DI) > 1; normal 1p and 11q
      • INSS stage 3; 365 days to 12 years of age; MYCN-NA; FH; normal 1p and 11q
      • INSS stage 4S; age < 365 days; MYCN-NA; FH; DI >1; normal 1p and 11q; clinically symptomatic

    • Group 3

      • INSS stage 2A/2B; < 50% resected or biopsy only; ≤ 12 years of age; MYCN-NA; any histology and ploidy; 1p loss of heterozygosity (LOH) and/or unb11q LOH (or data missing for either)
      • INSS stage 3; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH (or data missing for either)
      • INSS stage 3; age < 365 days; MYCN-NA; DI = 1 and/or unfavorable histology (UH); normal 1p and 11q
      • INSS stage 3; 365 days to 12 years of age; MYCN-NA; FH; 1p LOH and/or unb11q LOH (or data missing for either)
      • INSS stage 4; age < 365 days; MYCN-NA; FH; DI > 1; normal 1p and 11q
      • INSS stage 4S; age < 365 days; MYCN-NA; either UH and any ploidy or FH and DI = 1; normal 1p and 11q
      • INSS stage 4S; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH (or data missing for either); clinically symptomatic

    • Group 4

      • INSS stage 3; age < 365 days; MYCN-NA; DI = 1 and/or UH; 1p LOH and/or unb11q LOH (or data missing for either)
      • INSS stage 3; age 365 to < 547 days; MYCN-NA; UH; any ploidy; any 1p and 11q
      • INSS stage 4, age < 365 days; MYCN-NA; DI = 1 and/or UH; any 1p and 11q
      • INSS stage 4; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH (or data missing for either)
      • INSS stage 4; age 365 to < 547 days; MYCN-NA; FH; DI > 1; any 1p and 11q
      • INSS stage 4S; age < 365 days; MYCN-NA; UH and any ploidy or FH and DI = 1; 1p LOH and/or unb11q LOH (or data missing for either)

      • INSS stage 4S; age < 365 days; unknown or incomplete biologic features

        8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim.

Patients < 12 months of age with stg 3, 4, or 4S disease who achieve a very good PR (VGPR) to chemo (with the exception of resolution of skin or liver metastases in stage 4S patients) proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.

  • Must already be enrolled on protocol COG-ANBL00B1

    • Simultaneous enrollment on COG-ANBL00B1 and this study allowed for clinical situations in which emergent treatment may be indicated including, but not limited to, the following criteria:

      • Epidural or intraspinal tumors with existing or impending neurologic impairment
      • Periorbital or calvarial-based lesions with existing or impending cranial nerve impairment
      • Anatomic or mechanical compromise of critical organ function by tumor (e.g., abdominal compartment syndrome, urinary obstruction)
      • Asymptomatic but, in the opinion of the treating physician, it is in the patient's best interest to begin chemotherapy immediately due to impending risk of neurologic impairment or organ dysfunction

  • If patient receives study chemotherapy prior to undergoing diagnostic biopsy, the biopsy must be performed within 96 hours of beginning study therapy

    • The only exception to this requirement is for patients with stage 4S disease who are considered too ill to undergo a diagnostic procedure will be waived the requirement for diagnostic tissue submission but will still need to be enrolled on COG-ANBL00B1

      • For patients with stage 4S disease who are very ill and in whom an open biopsy to obtain tissue for diagnosis and biologic studies is considered medically contraindicated, every effort should be made to obtain some tumor tissue by either fine-needle aspiration of a metastatic site of disease and/or sampling of involved bone marrow, so that this tumor sample can be submitted for MYCN determination

  • Patients who require emergent therapy, either prior to the diagnostic biopsy or before biology features are available, can be enrolled simultaneously on COG-ANBL00B1 and COG-ANBL0531 to receive emergent protocol therapy

    • In emergent circumstances, COG-ANBL0531 protocol therapy may be initiated prior to enrollment on study as long as the patient has neuroblastoma by clinical diagnosis, all other COG-ANBL0531 eligibility criteria are met, and the COG-ANBL0531 Initial Therapy consent has been signed prior to starting protocol therapy; in this circumstance ANBL0531 enrollment must occur within 4 working days of starting protocol therapy

    • Clinical situations in which emergent enrollment and treatment may be indicated include, but are not limited to, the following circumstances:

      • Epidural or intraspinal tumors with existing or impending neurologic impairment
      • Periorbital or calvarial-based lesions with existing or impending cranial nerve impairment
      • Anatomic or mechanical compromise of critical organ function by tumor (e.g., abdominal compartment syndrome, urinary obstruction)
      • Evolving hepatomegaly in infants less than 2 months of age

PATIENT CHARACTERISTICS:

  • See Disease Characteristics

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • No other prior chemotherapy or radiotherapy with the exception of dexamethasone
  • No participation in another COG study with tumor therapeutic intent
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00499616


Locations
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Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Study Chair: Clare Twist, MD Lucile Packard Children's Hospital at Stanford University Medical Center
Study Chair: Mary Lou Schmidt, MD University of Illinois at Chicago
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Layout table for additonal information
Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00499616    
Other Study ID Numbers: ANBL0531
COG-ANBL0531 ( Other Identifier: Children's Oncology Group )
NCI-2009-00400 ( Other Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: July 11, 2007    Key Record Dates
Results First Posted: June 27, 2017
Last Update Posted: July 6, 2021
Last Verified: June 2021
Keywords provided by Children's Oncology Group:
regional neuroblastoma
disseminated neuroblastoma
stage 4S neuroblastoma
localized unresectable neuroblastoma
localized resectable neuroblastoma
Additional relevant MeSH terms:
Layout table for MeSH terms
Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cyclophosphamide
Carboplatin
Doxorubicin
Liposomal doxorubicin
Etoposide
 Topotecan
Isotretinoin
Lenograstim
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors